Pharmacological actions of nobiletin in the modulation of platelet function

Background and Purpose The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin in the modulation of platelet function. Experimental Approach The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. The fibrinogen binding, α-granule secretion and calcium mobilisation assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Key Results Nobiletin was shown to supress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilisation and thrombus formation. Nobiletin was shown to extend bleeding time in mice and reduce the phosphorylation of Akt and PLCγ2 within the collagen receptor (GPVI) - stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of VASP, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. Conclusions and Implications This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore nobiletin may represent a potential antithrombotic agent of dietary origins.

Dominant role of greenhouse-gas forcing in the recovery of Sahel rainfall

Sahelian summer rainfall, controlled by the West African monsoon, exhibited large-amplitude multidecadal variability during the twentieth century. Particularly important was the severe drought of the 1970s and 1980s, which had widespread impacts1–6. Research into the causes of this drought has identified anthropogenic aerosol forcing3,4,7 and changes in sea surface temperatures (SSTs; refs 1,2,6,8–11) as the most important drivers. Since the 1980s, there has been some recovery of Sahel rainfall amounts2–6,11–14, although not to the pre-drought levels of the 1940s and 1950s. Here we report on experiments with the atmospheric component of a state-of-the-art global climate model to identify the causes of this recovery. Our results suggest that the direct influence of higher levels of greenhouse gases in the atmosphere was the main cause, with an additional role for changes in anthropogenic aerosol precursor emissions. We find that recent changes in SSTs, although substantial, did not have a significant impact on the recovery. The simulated response to anthropogenic greenhouse-gas and aerosol forcing is consistent with a multivariate fingerprint of the observed recovery, raising confidence in our findings. Although robust predictions are not yet possible, our results suggest that the recent recovery in Sahel rainfall amounts is most likely to be sustained or amplified in the near term.

Prostate cancer: important steps and considerations in the design of therapeutic vaccines

Vaccine-based immunotherapy can increase the overall survival of patients with advanced prostate cancer. However, the efficacy of vaccine-elicited anticancer immune responses is heavily influenced by the physical, nutritional, and psychological status of the patient. Given their importance, these parameters should be carefully considered for the design of future clinical trials testing this immunotherapeutic paradigm in prostate cancer patients.

Choosing international linkage strategies in the electronics industry: the role of multinational experience

This paper examines how different aspects of multinational experience affect the choice of international linkage strategy. Integrating transaction cost and dynamic efficiency considerations, we empirically test the determinants of the choice between acquisitions, joint ventures (JV), and strategic alliances (SA) for the world’s largest electronics corporations in 1993–1997. We show that “country specific experience” increases the probability of commitment intensive linkage modes (such as acquisitions and joint ventures), while a positive effect on strategic alliances is caused by “variety experience”, deriving from the heterogeneity of international contexts, and by “internationalisation experience” reflecting overall involvement in international markets.

'The house of books': libraries and archives in Ancient Egypt

In 1957, John Sperry Jr. published an article in Libri entitled “Egyptian libraries: a survey of the evidence.” Some 55 years on, this article revisits the subject, taking into account research undertaken in the field of Egyptology over the last half a century. Based on an extended essay written for the online Certificate in Egyptology course at the University of Manchester, this article considers the evidence for the existence of “institutional” (that is, created for the use and functioning of the state) libraries and archives in Ancient Egypt throughout the dynastic period (c.3500−30 B.C.); their history, purpose and, to some extent, their administration. It also considers an aspect not explored in Sperry’s article, that of “private” libraries in Ancient Egypt (texts collected by an individual for their own personal use). Whilst estimated literacy levels within the general population precluded the widespread collection of texts for personal edification, there is evidence to suggest that private libraries were present in Ancient Egypt. The article concludes with a brief assessment of the legacy of these ancient libraries and their influence on the creation of the Library of Alexandria, in both its ancient and modern manifestations.

Unwriting food labels: discursive challenges in the regulation of package claims

This article examines the challenges resulting from the regulation of written discourse on food packages. It uses as a case study Hong Kong’s strict new food-labeling law that requires distributers and retailers to remove certain nutritional claims from packages of imported food before they sell them. This practice of redacting unlawful text on packages requires that distributers and retailers engage in complex processes of discursive reasoning, and it some- times results in packages that are difficult for customers to interpret. The case study highlights important issues in the regulation of commercial texts concerning collaboration, intertextuality, and the conflicts that can arise when the principals, authors, and animators of such texts have different agendas.

Robust multimodal face and fingerprint fusion in the presence of spoofing attacks

Anti-spoofing is attracting growing interest in biometrics, considering the variety of fake materials and new means to attack biometric recognition systems. New unseen materials continuously challenge state-of-the-art spoofing detectors, suggesting for additional systematic approaches to target anti-spoofing. By incorporating liveness scores into the biometric fusion process, recognition accuracy can be enhanced, but traditional sum-rule based fusion algorithms are known to be highly sensitive to single spoofed instances. This paper investigates 1-median filtering as a spoofing-resistant generalised alternative to the sum-rule targeting the problem of partial multibiometric spoofing where m out of n biometric sources to be combined are attacked. Augmenting previous work, this paper investigates the dynamic detection and rejection of livenessrecognition pair outliers for spoofed samples in true multi-modal configuration with its inherent challenge of normalisation. As a further contribution, bootstrap aggregating (bagging) classifiers for fingerprint spoof-detection algorithm is presented. Experiments on the latest face video databases (Idiap Replay- Attack Database and CASIA Face Anti-Spoofing Database), and fingerprint spoofing database (Fingerprint Liveness Detection Competition 2013) illustrate the efficiency of proposed techniques.

Copyright exceptions and contract in the UK: the impact of recent amendments

In June and October 2014 a number of amendments to the Copyright, Designs and Patents Act 1988 came into effect, introducing new copyright exceptions and amending several existing exceptions. Whilst following recent judicial review the private copying exception has been quashed, many of the remaining new exceptions significantly alter the relationship between copyright exceptions and contract, making contractual terms unenforceable where those terms restrict users from taking advantage of an exception. This paper explores the rationale for the UK amendments and considers whether the changes, as implemented, prevent rightsholders from contracting out of exceptions and whether they increase the clarity of the copyright system.

Modelling spectral reflectance of open cork oak woodland: a simulation analysis of the effects of vegetation structure and background

This study analyses the influence of vegetation structure (i.e. leaf area index and canopy cover) and seasonal background changes on moderate-resolution imaging spectrometer (MODIS)-simulated reflectance data in open woodland. Approximately monthly spectral reflectance and transmittance field measurements (May 2011 to October 2013) of cork oak tree leaves (Quercus suber) and of the herbaceous understorey were recorded in the region of Ribatejo, Portugal. The geometric-optical and radiative transfer (GORT) model was used to simulate MODIS response (red, near-infrared) and to calculate vegetation indices, investigating their response to changes in the structure of the overstorey vegetation and to seasonal changes in the understorey using scenarios corresponding to contrasting phenological status (dry season vs. wet season). The performance of normalized difference vegetation index (NDVI), soil-adjusted vegetation index (SAVI), and enhanced vegetation index (EVI) is discussed. Results showed that SAVI and EVI were very sensitive to the emergence of background vegetation in the wet season compared to NDVI and that shading effects lead to an opposing trend in the vegetation indices. The information provided by this research can be useful to improve our understanding of the temporal dynamic of vegetation, monitored by vegetation indices.

Consent and the use of force: an examination of ‘intervention by invitation’ as a basis for US drone strikes in Pakistan, Somalia and Yemen

Drone strikes are becoming a key feature of the United States’ global military response to nonstate actors, and it has been widely adduced that these strikes have been carried out with the consent of the host states in which such non-state actors reside. This article examines the degree to which assertions of consent (or ‘intervention by invitation’), provided as a justification for drone strikes by the United States in Pakistan, Yemen and Somalia, can be said to accord with international law. First the article provides a broad sketch of the presence of consent in international law. It then analyses in detail the individual elements of consent as provided by Article 20 of the International Law Commission Draft Articles of State Responsibility. These require that consent should be ‘valid’, given by the legitimate government and expressed by an official empowered to do so. These elements will be dealt with individually, and each in turn will be applied to the cases of Pakistan, Yemen and Somalia. Finally, the article will examine the breadth of the exculpatory power of consent, and the extent to which it can preclude the wrongfulness of acts carried out in contravention of international law other than the prohibition of the use of force under Article 2(4) of the Charter of the United Nations.

Advancements in decadal climate predictability: the role of nonoceanic drivers

We review recent progress in understanding the role of sea ice, land surface, stratosphere, and aerosols in decadal-scale predictability and discuss the perspectives for improving the predictive capabilities of current Earth system models (ESMs). These constituents have received relatively little attention because their contribution to the slow climatic manifold is controversial in comparison to that of the large heat capacity of the oceans. Furthermore, their initialization as well as their representation in state-of-the-art climate models remains a challenge. Numerous extraoceanic processes that could be active over the decadal range are proposed. Potential predictability associated with the aforementioned, poorly represented, and scarcely observed constituents of the climate system has been primarily inspected through numerical simulations performed under idealized experimental settings. The impact, however, on practical decadal predictions, conducted with realistically initialized full-fledged climate models, is still largely unexploited. Enhancing initial-value predictability through an improved model initialization appears to be a viable option for land surface, sea ice, and, marginally, the stratosphere. Similarly, capturing future aerosol emission storylines might lead to an improved representation of both global and regional short-term climatic changes. In addition to these factors, a key role on the overall predictive ability of ESMs is expected to be played by an accurate representation of processes associated with specific components of the climate system. These act as “signal carriers,” transferring across the climatic phase space the information associated with the initial state and boundary forcings, and dynamically bridging different (otherwise unconnected) subsystems. Through this mechanism, Earth system components trigger low-frequency variability modes, thus extending the predictability beyond the seasonal scale.

An idealized study of coupled atmosphere-ocean 4D-Var in the presence of model error

Atmosphere only and ocean only variational data assimilation (DA) schemes are able to use window lengths that are optimal for the error growth rate, non-linearity and observation density of the respective systems. Typical window lengths are 6-12 hours for the atmosphere and 2-10 days for the ocean. However, in the implementation of coupled DA schemes it has been necessary to match the window length of the ocean to that of the atmosphere, which may potentially sacrifice the accuracy of the ocean analysis in order to provide a more balanced coupled state. This paper investigates how extending the window length in the presence of model error affects both the analysis of the coupled state and the initialized forecast when using coupled DA with differing degrees of coupling. Results are illustrated using an idealized single column model of the coupled atmosphere-ocean system. It is found that the analysis error from an uncoupled DA scheme can be smaller than that from a coupled analysis at the initial time, due to faster error growth in the coupled system. However, this does not necessarily lead to a more accurate forecast due to imbalances in the coupled state. Instead coupled DA is more able to update the initial state to reduce the impact of the model error on the accuracy of the forecast. The effect of model error is potentially most detrimental in the weakly coupled formulation due to the inconsistency between the coupled model used in the outer loop and uncoupled models used in the inner loop.